ACE Inhibitor Dosing Considerations in CHARM

1
ACE Inhibitor Dosing Considerations in CHARM

• John J.V. McMurray, MD
• Professor of Medical CardiologyWestern
  InfirmaryGlasgow
• Scotland
• UK

2
What is Optimal Treatment With an ACE Inhibitor?

• Which drug? What dose?
• The evidence-base randomized controlled outcome
  trials
• Studies looking at higher than evidence-based
  doses?

3
Which drug? The ACE inhibitors Used in Randomized
Controlled Outcome Trials in Acute MI and CHF

• Captopril (SAVE)
• Ramipril (AIRE)
• Trandolapril (TRACE)
• Lisinopril (ATLAS, GISSI 3)
• Enalapril (CONSENSUS, SOLVD, VHeFT II)

CHARM investigators were advised that these were
the preferred ACE inhibitors at investigator
meetings and in study protocol
4
Clinical Programme ProtocolCHARM
AddedInstructions to Investigators on Dosing of
ACEi
46
Clinical programme protocol-CHARM

• the investigator is asked to attempt to
  optimize therapy for each individual patient. In
  this component study baseline therapy with an ACE
  inhibitor is mandatory. No dose of an ACE
  inhibitor is, however, mandated. The investigator
  is free to choose the dose of ACE inhibitor that
  is optimum for each patient, based on
  tolerability (e.g. taking into account blood
  pressure, renal function etc.) and information
  from the large randomized trials. The
  investigator is reminded that these trials had
  target ACE inhibitor doses (Appendix 1) higher
  than those commonly used in clinical practice.
  Furthermore, the recent ATLAS study has also
  shown that larger ACE inhibitor doses reduce
  morbidity to a greater extent than lower doses.

5
What dose? Randomized Controlled Outcome Trials
Using Forced Titration of ACE Inhibitors in Acute
MI and CHF
Trial ACEinhibitor Target dose, mg Mean daily dose, mg
SAVE (1992) captopril 50 tid 121
SOLVD-T (1991) enalapril 10 bid 16.6
AIRE (1993) ramipril 5 bid 8.7
TRACE (1995) trandolapril 4 qd 3
ATLAS (1999) lisinopril 2.5 - 5.0 qd 32.5 - 35 qd 3.2 22.5
GISSI 3 (1994) lisinopril 10 mg qd N/A
These were the target doses CHARM investigators
advised to aim for at investigator meetings
and in protocol
US and European guidelines recommend a target
dose of 20 mg/d.
6
Use of ACE Inhibitors What happened in CHARM
Added?

• Investigators were provided with a list of
  preferred ACE inhibitors and doses, based on
  randomized controlled outcome trials
• Investigators asked to ensure patients on an
  individualized optimum dose of ACE inhibitor at
  baseline
• Stable dose of ACEi for 30 days

7
Which drug? The ACE inhibitors Used in Randomized
Controlled Outcome Trials in Acute MI and CHF

• Captopril (SAVE)
• Ramipril (AIRE)
• Trandolapril (TRACE)
• Lisinopril (ATLAS, GISSI 3)
• Enalapril (CONSENSUS, SOLVD, VHeFT II)

CHARM investigators were advised that these were
the preferred ACE inhibitors. Approx. 80 of
patients were treated with one of these
evidence-based ACE inhibitors
8
FDA Approved ACE Inhibitors For Heart Failure
ACE inhibitor ACE inhibitor CHARM Added CHARM Added
Proportion of patientsat baseline, FDA labeled HF dose Baseline mean dose
Proportion of patientsat baseline, mg/d mg/d
Enalapril 27 5 - 20 (40) 17
Lisinopril 19 5 - 40 (40) 18
Captopril 17 150 - 300 (450) 83
Ramipril 11 10 7
Trandolapril 6 4 2
Perindopril 6 NA 4
Quinapril 5 20 - 40 25
Fosinopril 5 20 - 40 20
Benazepril 3 NA 26
Cilazapril, Moexipril 1 NA
NA Not FDA approved for heart failure.
9
Dose of ACE Inhibitor What happened in CHARM
Added?

• Investigators reported that 96 of patients were
  taking an individualized, optimum, dose of ACE
  inhibitor at baseline (CRF check box)
• Supporting evidence?

10
Dose of ACE Inhibitor Achieved in CHARM Added
Compared to Randomized Outcome Trials Using
Forced Titration
Trial ACE-inhibitor ( in CHARM Added) Mean dose in outcome trial (mg) Mean dose in CHARM-Added (mg)
SOLVD Enalapril (27) 16.6 17.0
ATLAS Lisinopril (19) 3.2 22.5 17.7
GISSI 3 Lisinopril N/A 17.7
SAVE Captopril (17) 121 82.5
AIRE Ramipril (11) 8.7 7.1
TRACE Trandolapril (6) 3.0 2.5
US and European guidelines recommend target
dose of 20 mg/d.
11
Dose of ACE Inhibitor (Enalapril) Achieved in
CHARM Added Compared to Randomized Outcome Trials
Using Forced Titration
Trial N Target dose, mg Mean daily dose, mg
CONSENSUS (1987) 127 20 bid 18.4
SOLVD-T (1991) 1284 10 bid 16.6
SOLVD-P (1992) 2111 10 bid 16.7
V-HeFT II (1991) 403 10 bid 15.0
OVERTURE (2002) 2884 10 bid 17.7
CARMEN (2004) 190 E only 191 ECarv 10 bid 10 bid 16.8 14.9
CHARM Added 680 - 17.0
N.B. active run-in 49 reached target dose.
12
CHARM Investigators Did Optimize ACE Inhibitor
Dose
Daily dose of ACE inhibitor in CHARM Added
compared to other outcome studies using add-on
therapy
Trial MERIT-HF CIBIS-2 RALES CHARM Added
Enalapril 14 12.7 15 17.0
Captopril 64 48.3 62 82.5
Lisinopril 16.5 12.8 14.3 17.7
Ramipril 6.2 4.2 - 7.1
Personal communication.
13
ACE Inhibitor Doses in CHFCHARM Added Compared
to Community and Hospital Practice
Study/country/setting Captopril Enalapril Lisinopril Ramipril
McGrae, et al, 1997 (US hospital, n 612) 21 7.7 - -
Smith, et al, 1998 (US community CVHS, n 129) 54 8.9 11.7 -
McAlister, et al, 1999 (Canada specialist HF clinic, n 566) 62.1 10.7 10.3 -
Chen, et al, 2001 (US hospital, n 554) 58.8 12.0 10.0 -
EuroHF study, 2004 (Europe hospital n 11,304) 57.6 14.4 12.3 5.1
IMPROVEMENT-HF, 2002 (UK Community, n 599) 49.6 13.8 11.2 4.6
CHARM Added (n 2548) 82.5 17.0 17.7 7.1
14
Would a Larger Than Evidence-Based Dose of an ACE
Inhibitor Have Made a Difference?
ACE inhibitor dose response studies

• Many ACE inhibitor dose-response studies
• Most compared low dose(s) to a proven,
  evidence-based, dose (eg, NETWORK) or low
  dose(s) to a medium/high dose eg, (ATLAS)
• What about comparison of a proven,
  evidence-based, dose to an even higher dose?

15
Larger Than Evidence-Based Doses of ACE
Inhibitors Two Questions

• Can they be achieved? Note
• SOLVD-T target enalapril 10 mg bid 49 achieved
  target mean dose
  achieved 16.6 mg
• CONSENSUS target 20 mg bid 22 achieved
  target mean dose achieved
  18.4 mg
• Is there additional benefit?

16
Enalapril 20 mg/d vs 60 mg/d trial

• 248 patients with CHF (mean LVEF 19) randomized
  to standard-dose (20 mg/d) or high-dose (60 mg/d)
  enalapril. 12 months follow-up
• Doses achieved 17.9 mg/d and 42.5 mg/d,
  respectively
• 72.5 and 32.5, respectively reached target dose
  by 3 months
• No statistically significant or clinically
  meaningful difference between groups for change
  in blood pressure, heart rate, LVEF or NYHA class
• No significant difference in any clinical
  outcome (but small numbers)

Nanas J, et al. J Am Coll Cardiol.
2000362090-2095.
17
Enalapril 20 mg/d vs 60 mg/d TrialDeath or HF
HospitalizationEvent Free Survival
100
80
20 mg/d
60 mg/d
60
Freedom from death or HF hospitalization,
40
20
p 0.645
0
0
2
4
6
8
10
12
Time (months)
Nanas J, et al. J Am Coll Cardiol.
2000362090-2095.
18
Summary Optimal ACE Inhibitor Treatment

• CHARM Added patients received
• Evidence-based ACE inhibitor (80 of patients)
• ACE inhibitor doses comparable to those achieved
  with forced titration (eg, 17 mg of enalapril)
• Higher doses of ACE inhibitor than in other
  recent add-on treatment trials
• Much higher doses of ACE inhibitor than in
  ordinary clinical practice
• No evidence that exceeding proven dose of ACE
  inhibitor is advantageous

19
Conclusion CHARM Added ACE Inhibitor Dosing

• Evidence-based treatment with ACE inhibitor
  advocated by protocol and used by investigators
• CHARM Added did test the hypothesis of whether
  adding an ARB to a evidence-based dose of ACE
  inhibitor would offer further clinical benefit